Background: A growing number of Veterans are presenting to the Veterans Health Administration (VHA) for the treatment of Bipolar disorder (BP) and co-occurring substance use disorders (SUDs), with prevalence of SUDs in patients with BP up to 60%. This comorbidity is associated with increased symptom severity, poorer treatment outcomes, and greater use of costly health services such as psychiatric hospitalization. Significance/Impact: Veterans who transition from psychiatric hospitalization to outpatient care are at heightened risk for treatment nonadherence, mood/substance relapse, deaths due to opioid overdose, and suicide. Nonadherence to treatment is a significant problem among patients with BP, which is further magnified among those with SUDs. Nonadherence leads to increased need for psychiatric readmission, with BP patients recently discharged from inpatient care particularly likely to discontinue pharmacotherapy, relapse to substances, and attempt suicide. Of particular concern are disproportionately greater rates of suicide in Veterans with BP relative to those with other mental health conditions. Veterans with BP who use substances, particularly alcohol and opioids, have the highest suicidality and mortality rates. To date, there is little research on effective and feasible behavioral aftercare interventions designed to improve treatment adherence in this high-risk, comorbid population at the critical period following hospital discharge. Innovation: Empirical work suggests that the ?Integrated Treatment Adherence Program? (ITAP) may be an ideal therapeutic approach to improve treatment adherence and clinical outcomes in Veterans at the critical period of transition to outpatient care following hospitalization. ITAP is an innovative psychosocial intervention developed by our team designed to improve treatment adherence and reduce suicidality, bipolar symptoms, and substance abuse among high-risk patients, addressing HSR&D major research priorities. ITAP combines in-person engagement sessions with follow-up phone contacts and significant other involvement as an adjunct to treatment as usual over 6 months post-hospitalization. Methodology: The proposed Hybrid Type 1 Effectiveness-Implementation Trial will evaluate the effectiveness of ITAP in a sample of 140 Veterans with BP-SUD, randomized to receive either the ITAP intervention or a Safety Assessment and Follow-up Evaluation (SAFE) comparison condition, both delivered as adjuncts to VHA treatment as usual. Veterans will be recruited from the Providence VAMC inpatient psychiatric unit and assessed at baseline and at 3 (mid-treatment), 6 (post-treatment), and 9-month follow-up. The Primary Aim is to test the hypotheses that participants randomized to receive ITAP, relative to SAFE, will evidence improved treatment outcomes at post- treatment, maintained through follow-up. Primary outcomes are: 1) greater treatment adherence defined by (a) percent missed medications doses/month (based on electronic monitoring) and (b) percent missed VHA mental health appointments/month. Secondary outcomes are: (2) reduced suicidality and number of psychiatric hospitalizations/ER visits; and (3) lower depressive and manic symptoms, lower percentage of alcohol and drug use days, and improved overall psychosocial functioning. The Secondary Aims are to identify the mechanisms of action targeted by ITAP, moderators of treatment effects, and perceptions of key stakeholders and contextual factors that may reduce barriers and increase organizational readiness for implementation of ITAP in the VHA. Next Steps/Implementation: If shown effective and in cooperation with our operational partners, the next steps for ITAP would be to conduct a Hybrid Type 3 Implementation Trial to test specific implementation strategies within a multi-site study and to develop an implementation blueprint for ITAP-based standard of care within the VHA. Determining whether ITAP is an effective adjunctive treatment directly addresses the need for improved adherence to evidence-based mental health and substance use treatments and the need for effective suicide prevention interventions in Veterans. Should ITAP prove effective, we will work with our operational partners to prioritize ITAP?s ultimate dissemination and implementation within VHA.